This laboratory studies the mechanisms by which the thyrotropin receptor (TSHR) regulates both thyroid growth and function, the mechanisms by which self-tolerance is maintained during hormonally induced growth and function, the development of thyroid autoimmunity or tumors when these processes fail, and the relationships of thyroid autoimmunity to other autoimmune diseases, i.e. diabetes and lupus. Improved diagnostic procedures and therapeutic modalities are pursued in these areas. TSHR/gonadotropin receptor structure abnormalities underlying genetic diseases are also studied. This year, cell-cycle-dependent, TSH-induced growth has been linked to activation of HMG CoA reductase, gerranylation of rho, and degradation of the p27 cyclin inhibitor. Also, two transgenic animal systems overexpressing Gs or Gq thyroid signals have been created and shown to cause hyperplasia not thyroid tumors; crossbreeding is testing the results of dual signal overexpression in the tumor development process. Monoclonal antibody and receptor chimera studies in Graves' and Hashimoto's patients have defined epitopes for TSHRAbs which inhibit TSH binding (TBIIs), have related them to stimulating and blocking TSHRAbs, and have defined subsets of TSHRAbs whose presence can be used to predict the success of antithyroid drug therapy. A Graves' model has been used to define T cell epitopes important for autoantibody development and T cell clones isolated. The hypothesis that common cis elements and transfactors coregulate the TSHR and major histocompatibility class I and class II genes has been further supported; abnormal regulation has been linked to the development of autoimmunity. and a potential mechanism for the loss of negative regulation in humans is being tested. A drug 10 to 100-fold more potent than methimizole with potential for treating autoimmune disease (thyroid AD, lupus, psoriasis, autoimmune colitis, myositis, and diabetes), as well as transplant rejection, is under in vivo animal testing.